Catechol Oxidase-Like Oxidation Chemistry of the 1–20 and 1–16 Fragments of Alzheimer’s Disease-Related β-Amyloid Peptide: Their Structure-Activity Correlation and the Fate of Hydrogen Peroxide^‡
da Silva, G. F. Z.; Tay, W. M. and Ming, L.-J.
J. Biol. Chem. 2005, 280, 16601-16609

The Cu⁺² complexes of the 1-16 and the 1-20 fragments of the Alzheimer’s disease-related β-amyloid peptide (CuAβ) show significant oxidative activities toward a catechol-like substrate trihydroxylbenzene and plasmid DNA cleavage.  The latter reflects possible oxidative stress to biological macromolecules, yielding supporting data to the pathological role of these soluble Aβ fragments.  The former exhibits enzyme-like kinetics and is dependent on [H₂O₂], exhibiting kcat of 0.066 s^–1 (6000 folds higher than the reaction without CuAβ) and k_cat/K_m of  37.2 M^–1s^–1 under saturating [H₂O₂] of ~0.24%.  This kinetic profile is consistent with metal-centered redox chemistry for the action of CuAβ.  A mechanism is proposed by the use of the catalytic cycle of dinuclear catechol oxidase as a working model.  Trihydroxylbenzene is also oxidized by CuAβ aerobically without H₂O₂, affording rate constants of 6.50 × 10^–3 s^–1 and 3.25 M^–1s^–1.  This activity is also consistent with catechol oxidase action in the absence of H₂O₂, wherein the substrate binds and reduces the Cu²⁺ center first, followed by O₂ binding to afford the μ-η²:η²-peroxo intermediate which oxidizes a second substrate to complete the catalytic cycle.  A tetragonally distorted octahedral metal coordination sphere with three coordinated His side chains and some specific H-bonding interactions is concluded from the electronic spectrum of CuAβ, hyperfine-shifted ¹H NMR spectrum of CoAβ, and molecular mechanics calculations.  The results presented here are expected to add further insight into the chemistry of metallo-Aβ which may assist better understanding of the neuropathology of Alzheimer’s disease. 

^‡  LJM dedicates this article to his mother and to Dr. Shwu-Yeng Lin, who with great patience and kindness have been caring for their beloved better halves through some very difficult times of “losing minds”.  GFZS dedicates this article to Ayres Baptista Mello and family, whose struggle with Alzheimer's disease has fueled the author's desire in gaining better understanding of the mechanisms of this disease at the molecular level.

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